tbuckley/cabot-search huggingface dataset:
INNV-38. PREDICTING THE CLINICAL PHENOTYPE IN <i>NF2</i> RELATED SCHWANNOMATOSIS PATIENTS
Authors: Arianna Borghi, Nayma Rosati, Rosina Paterra, Igrazio Vetrano, Vittoria Nazzi, Marco Moscatelli, Antonio Silvani, Marica Eoli
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Different genetic scores have been proposed to predict the phenotype of NF2 related Schwannomatosis (NF2 -SCHW MIM # 101000) , a rare autosomal dominant familial cancer syndromes caused by pathogenic variants of the NF2 gene. The UK NF2 Reference Group proposed the Genetic Severity Score (GSS) based on the type and location of NF2 germline variant observed. Catasus et al. suggested a new score based also on a functional assay of Merlin and its downstream pathways (FGSS). Recently Teranish et al. used targeted deep sequencing to predict functional prognosis in those patients. Material and METHODS 70 patients (median age 40) were identified by scanning the electronic NF2-SCHW patient database at Fondazione IRCCS C. Besta,. The median follow-up was 14 yrs. Clinical diagnosis was established following the Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis”. All patients underwent NF2, SMARCB1 and LZTR1 mutational screening by NGS and MPLA analysis using blood DNA or the tissue of two different tumors when available. NF2 gene germline pathogenic were found in 45 subjects (64%), in most cases NF2 point mutations, but in 4 cases and whole gene deletions was observed and in 2 a ring NF2 chromosome was identified, in four cases a mosaic NF2-SCH was identified and in 21 (30%) patients no pathogenic variant was found. We assessed NF2 clinical phenotype in relation to the UK GSS and FGSS to validate their use. RESULTS The disease phenotype differed significantly depending both on clinical and genetic factors.. GSS and FGSS showed significant correlation with several measures, allowing stratification of patients with severe and mild disease but not with moderate phenotype. Furthermore, we provided evidence on correlation between whole NF2 deletion extent and phenotype severity. Large cohorts of NF2-SCHW patients are needed to identify more accurate scores.
QLTI-04. LINKING DATA FROM A BRAIN CANCER CLINICAL REGISTRY (BRAIN) WITH THE STATE-BASED REGISTRY OF BIRTHS DEATHS MARRIAGES: IMPROVING THE QUALITY OF CLINICAL REGISTRY SURVIVAL DATA
Authors: Samuel Smith, Kate Drummond, Anthony Dowling, Iwan Bennett, Ronnie Freilich, Claire Phillips, Elizabeth Ahern, Simone Reeves, Robert Campbell, Ian Collins, Julie Johns, Megan Dumas, Peter Gibbs, Lucy Gately
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Real-world data (RWD) collected routinely in clinical care forms the basis of cancer clinical registries. These registries are inclusive and provide valuable research outcomes, however missing data particularly survival compromise the accuracy of RWD. Here we explore the utility of data linkage to state-based registries to enhance the capture of survival outcomes. METHODS We reviewed prospectively collected data from consecutive patients with brain tumours in the Brain Tumour Registry Australia Innovation and Translation (BRAIN) database and included those treated in Victoria with no recorded date of death and no follow-up the preceding 6 months. Full name and birthdate were used to match patients in the BRAIN registry to those in the Victorian Births, Deaths and Marriages (BDM) Registry. Survival outcomes were compared, pre- and post-data linkage (DL). RESULTS Of the 7735 patients contained in BRAIN, 5435 patients (70.3%) met eligibility criteria and had no recorded date of death. 1611 (30%) of patients were matched with a date of death in BDM. More matches were found in tumours of highest malignant potential such as grade 4 glioma (67.2%), brain metastases (63.9%) and primary cerebral lymphoma (50.5%), compared with good-prognostic tumours such as meningioma (8.7%) and schwannoma (3.2%). Compared to post-DL, survival outcomes were significantly overestimated pre-DL for the entire cohort (30.3m vs 17m, p&amp;lt; .0001). This difference was most pronounced for Grade-3 glioma (93.7m vs. 38.1 p = 0.008) but significant differences were seen across all tumour types. CONCLUSION Using an Australian brain-tumour population, this is the first study to demonstrate the importance of improved RWD accuracy through linking state-based registries to comprehensive cancer registries. This missing death data significantly compromises the potential quality of audit and research projects, driving a repeated over-estimate of survival. Routine periodic DL to pertinent registries should be considered to ensure accurate reporting and interpretation of RWD.
RTID-08. A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY WITH ANTISENSE OLIGO IMV-001 TARGETING IGF-1R, VS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Ian Lee, Kevin Judy, Michael Schulder, Simon Hanft, Linton Evans, Julian Wu, Sonikpreet Aulakh, Eric Wong, Vijay Agarwal, Rohan Ramakrishna, J Bradley Elder, Brian Gill, Alfredo Quiñones-Hinojosa, Cameron Brennan, Raul Perez-Olle, Madhavi Diwanji, Gregory Pennock, Charles Scott, David Andrews, John Boockvar
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusion criteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.
RADT-35. STEREOTACTIC RADIOSURGERY FOR RESIDUAL, RECURRENT, AND METASTATIC HEMANGIOPERICYTOMAS: A SINGLE INSTITUTION EXPERIENCE
Authors: Kelly Yoo, David Park, Anand Veeravagu, Marco Lee, Neelan Marianayagam, Aroosa Zamarud, Xuejun Gu, Erqi Pollom, Scott Soltys, Steven Chang, Antonio Meola
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Hemangiopericytomas are infrequent vascular tumors originating from Zimmermann pericytes. The conventional treatment approach involves gross total resection (GTR), followed by adjuvant radiotherapy. Nevertheless, due to their tendency to infiltrate dural sinuses, high degree of vascularity, and anatomic inaccessibility, radical resection may be challenging with substantial risk of recurrence. To address this challenge, stereotactic radiosurgery (SRS) has been proposed as a promising adjuvant therapy. Objectives Our study aims to evaluate the effectiveness and safety of SRS as a potential treatment modality in patients with residual, recurrent, and metastatic hemangiopericytomas. METHODS From 1998 to 2023, 27 patients with 101 tumors underwent CyberKnife SRS at Stanford University Medical Center. The median age was 51 years at the time of treatment. The median follow-up period from SRS was 103 months (range: 6-250). All patients underwent upfront surgical resection. The median tumor volume was 1.5 cc. The median single-fraction equivalent dose (SFED) was 19 Gy. The SRS was administered at the 76% of the median isodose line (range: 64-89). RESULTS Of the 101 treated tumors, 24 (23.8%) progressed with a median time to recurrence of 30 months. At 10 years, the rates of local tumor control (LTC), overall survival (OS), and progression-free survival (PFS) were 74.3%, 80.8%, and 67%, respectively. In patients with residual lesions, the LTC rates were significantly greater when compared to those with residual or metastatic tumors. There was no significant difference between patients with residual, recurrent, and metastatic hemangiopericytomas in OS and PFS. Notably, no cases of radiation-induced adverse events were detected. CONCLUSION Our study provides the largest single-institutional retrospective series with hemangiopericytomas treated with SRS. SRS leads to excellent LTC, PFS, and OS at 10 years with negligible risk for adverse events. Therefore, it is an effective and safe management modality for patients with residual, recurrent, and metastatic hemangiopericytomas.
BIOM-54. VALIDATING MCM2 IMMUNOHISTOCHEMISTRY AS A SURROGATE MARKER FOR AGGRESSIVE MENINGIOMA
Authors: Allison Shelbourn, Nicholas Nuechterlein, Carolina Da Silva Parada, Jessica Eaton, Mallory Tucker, Manuel Ferreira, Patrick Cimino
Journal: Neuro-Oncology (2023)

Abstract Increasing efforts have focused to improve meningioma classification through various multi-omic analyses. One such recent study (Nassiri, et al, Nature, 2021) proposed an integrative molecular classification for meningiomas that included 4 molecular subtypes (MG1-4), with possible immunohistochemical surrogates for each subtype including S100B, ACADL, SCGN, and MCM2, respectively. While these immunohistochemical surrogates have been proposed for meningioma risk-stratification, their clinical utility has not been thoroughly tested. In this study, we sought to evaluate the utility of these immunohistochemical markers for risk-stratification in an independent cohort of meningioma. Tissue microarrays containing meningioma tissues were constructed, immunohistochemically stained, and blindly scored. Our cohort included n = 142 tumors (CNS WHO: 1=93, 2=45, 3=4). Median age was 49 years (range 14-80 years) with 89 female and 53 male patients. We found that MCM2 immunopositivity was a univariate marker of poor prognosis (median progression-free survival 1.2 years) when compared to negative tumors (median progression-free survival 13.0 years). The other three markers (S100B, ACADL, SCGN) were not associated with survival. MCM2 staining held up as a significantly independent (p = 0.03) poor prognostic marker on multivariate Cox proportional hazard modeling including other histopathological features: CNS WHO grade, brain invasion, mitotic index, and tumor size. Although MCM2 staining was independent of CNS WHO grade, all 4 of the CNS WHO 3 meningiomas were positive for MCM2. MCM2-positive tumors had a higher average mitotic count (6.1 mitoses/10hpf) compared to MCM2-negative tumors (1.8 mitoses/10hpf) (p = 0.0002, two-tailed t test). There was no difference between MCM2-positive and MCM2-negative meningiomas in relation to maximum tumor size (4.9cm and 4.2cm, respectively) and mean age (51.71 years and 50.34 years, respectively). In summary, in our cohort we found MCM2 immunopositive staining (surrogate marker for high-risk molecular subtype M4) to be an independently poor prognostic biomarker in meningioma when accounting for other well-established histopathological characteristics.
EXTH-13. ENHANCING INDUCED NEURAL STEM CELL-BASED TRAIL THERAPY FOR GLIOBLASTOMA THROUGH COMBINATION WITH THE NOVEL SENSITIZING AGENT TR-107
Authors: Morrent Thang, Clara Mellows, Breanna Mann, Lauren Kass, Sabrina Daglish, Emily Fennell, Alison Mercer-Smith, Alain Valdivia, Lucas Aponte-Collazo, Lee M Graves, Andrew B Satterlee, Shawn Hingtgen
Journal: Neuro-Oncology (2023)

Abstract Tumor-homing neural stem cell therapy (tNSC) is emerging as a promising treatment for aggressive cancers of the brain. Despite their success, developing tNSC therapies that maintain durable tumor suppression remains a challenge. Here, we report a new synergistic combination regimen where the novel agent TR107 augments induced NSC-TRAIL therapy (hiNeuroS-TRAIL) in models of the incurable brain cancer glioblastoma (GBM). We found that the combination of hiNeuroS-TRAIL and TR-107 synergistically upregulated caspase markers and restored the sensitivity to the intrinsic apoptotic pathway by significantly downregulating inhibitory pathways associated with chemoresistance and radioresistance in GBM. This combination regimen showed dramatic tumor suppression and enhancement of survival of mice bearing human xenografts of both solid GBM and established invasive GBM. The combination also synergistically suppressed tumor growth in low-passage patient derived GBM cells established with an ex vivo brain slice platform. These findings elucidate a novel combination regimen and suggest combination of these clinically relevant agents may represent a new therapeutic option with increased potency for GBM patients.
CTNI-76. EFFICACY OF BRAF INHIBITOR PLIXORAFENIB (FORE8394) IN RECURRENT, PRIMARY CENTRAL NERVOUS SYSTEM TUMORS (PCNST)
Authors: Macarena de la Fuente, Nicholas Butowski, Jennie Taylor, Rona Yaeger, Frank Yung-Chin Tsai, Filip Janku, Carl Allen, Natraj Ammakkanavar, Glenn Michelson, Ping Jiang, Michael Paz, Alexia Tussay-Lindenberg, Kongming Wang, Stacie Peacock Shepherd, Irina Kline, Eric Sherman, Jordi Rodon
Journal: Neuro-Oncology (2023)

Abstract Plixorafenib, a selective potent BRAFi, is uniquely designed to disrupt BRAF dimers and evade paradoxical MAPK pathway activation. Thus, it inhibits both V600 and non-V600 BRAF alterations and may be less prone to toxicities and resistance typical of approved BRAFi. An approved BRAFi, when used with MEKi, has ORR 33% with mDOR 13.6=months and ORR=50% with DOR of 6-29 months in V600+ HGG and LGG, respectively (dabrafenib US Prescribing Information, 2023). Phase 1/2a is a single-arm study (NCT02428712) in patients (n=113) with BRAF-altered advanced tumors to assess safety, PK, and efficacy of oral plixorafenib 900-3600 mg/day alone or with cobicistat (CYP3A4/P-gp inhibitor). Symptomatic TEAEs (rash, pyrexia, myalgia) were low grade and infrequent relative to approved BRAFi. This pre-specified analysis (31Mar2023) was in MAPKi-naïve adults with BRAFV600+ PCNST. 22 patients with PCNST received plixorafenib: 9 LGG, 1 glioneuronal tumor (LGG/GNT; 5 V600+), 12 HGG (10 V600+). Treatment-emergent AEs (TEAEs, ≥ 20%) were limited to LFT changes, G1 increased creatinine, fatigue, headache, and nausea. Only one G3 event (increased ALT) occurred at the RP2D (n=7) showing better tolerability than dabrafenib. 10 BRAFV600+ MAPKi-naïve adults with PCNST (median age 45 yrs, 6 females, 9 non-Hispanic) were efficacy evaluable: 6 HGG (4 glioblastoma, 1 epithelioid glioblastoma, 1 anaplastic astrocytoma); 4 LGG/GNT (1 each: ganglioglioma, pilocytic astrocytoma, xanthoastrocytoma, neuroepithelial tumor). Prior anti-cancer treatments included surgery (8/10), radiotherapy (8/10), and systemic therapy (8/10, including temozolomide [n=8], bevacizumab [n=2], carboplatin [n=1], dendritic cell vaccine [n=1]). 1 was treatment-naïve (unresectable; declined radiation/chemotherapy). ORR=60% (6/10) including HGG=67% (4/6), LGG/GNT=50% (2/4); median time to response=1.94 months; 4/6 responders with DOR &amp;gt; 9 months; mPFS=34.1 months; median follow-up=10.3 months; 4/10 ongoing. Plixorafenib has a benign safety profile and leads to a high ORR and durable response in MAPKi-naïve BRAFV600+ PCNST. A phase 2 study is ongoing to confirm these findings (NCT05503797).
EOLP-01. TREATMENT OF HEADACHES IN GLIOMA: A SYSTEMATIC REVIEW OF CURRENT PRACTICES AND FUTURE DIRECTIONS
Authors: Nangorgo Coulibaly, Audrey Grossen, James Battiste
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Headaches are one of the most common morbidities in glioma reported in 36 to 62% of patients along the course of their disease. Gliomas represent 27% of primary CNS neoplasms and accounted for an average annual age-adjusted incidence rate of 6.0 per 100 000 population according to data collected between 2010 and 2014. OBJECTIVES: The goal of this review was to evaluate current treatment options for glioma patients presenting with headaches and identify current headache treatment methods that could play a role in those patients. METHODS A systematic review of studies involving headaches in patients with gliomas was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search was conducted on PubMed, Ovid Medline, and Embase databases through January 3rd, 2023, with the following search terms: (analgesic OR anti-inflammatory OR prophylaxis OR steroids) AND (headache) AND (glioma or glioblastoma) AND (treatment). For each patient, we extracted: the therapy used, its outcome, and any side effects. RESULTS There were 11 out of 195 articles included in the review. For the articles that were fully reviewed (n =93), the majority of the exclusions 49% (n=40) were due to lack treatment method for patients’ headache. The most reported treatment options were Analgesics (n=211), steroids (dexamethasone, n=116), Surgical resection (n=2), and CGRP inhibitor (Fremanezumab, n=1). Most of the included studies 55% (n=6) only discussed headache treatment in 1 patient with 67% (n=4) of them being case report highlighting the lack of evidence covering this topic. CONCLUSION Headache treatment in patients with gliomas is an area of neuro-oncology with much to be learned. There is a need to further study the etiology of headaches in order to provide effective treatment plans that could improve the quality of life in this patient population.
CSIG-12. GLIOMA MICROENVIRONMENT: FUNCTIONS, MOLECULAR MECHANISMS, AND THERAPEUTIC IMPLICATIONS
Authors: Zhaoshi Bao, Ying Zhang, Peng Wang, Chengjun Zheng, Zhiliang Wang, Wenhua Fan
Journal: Neuro-Oncology (2023)

Abstract Abstract Gliomas are the most common intracranial tumors in adults. The high mortality and disability rates place a heavy burden on society and the families of patients. The median survival of patients who have primary grade 4 glioma at the World Health Organization is only 14.6 months. Unlike primary glioblastoma (WHO grade 4, pGBM) which usually occurs in older adults, secondary glioblastoma (WHO grade 4, sGBM) with isotrate dehydrogenase (IDH) mutations typically progresses from low to high grades within 5-10 years of diagnosis. Although surgery, radiotherapy, and chemotherapy have almost become the standard treatment for gliomas, the prognosis of patients is still poor. In recent years, the immune microenvironment has gradually become a possible direction for tumor treatment, and treatment methods such as PD1/PDL1 inhibitors and tumor vaccines have emerged. Owing to the microenvironment around the intracranial tumor cells and the body tumor being different, the microenvironment cells have their specific characteristics, and there is a blood-brain barrier, immunotherapy for the glioma microenvironment has encountered a bottleneck. Here, we summarize the current tumor-associated microenvironment and the interactions between tumor and immune cells and introduce the current status of glioma-specific microenvironment and immunotherapy for glioma. Finally, we mentioned several recent microenvironment-related research advances by our team and looked forward to future glioma microenvironmental research.
PATH-30. GLIOMAS WITH FGFR ONCOGENIC ALTERATIONS: CLINICO-PATHOLOGICAL FEATURES, MANAGEMENT AND OUTCOMES IN PEDIATRIC, ADOLESCENT AND YOUNG ADULT PATIENTS.
Authors: Magimairajan Issai Vanan, Saranya Kakumanu, Marshall Pitz, Craig Harlos, Colin Kazina, Patrick McDonald, Annie Drapeau, Anthony Kaufmann, Aoife O'Carroll, Qi Xu, Tina Drimes, Cathy Bourne, Jessica Streilein, Namita Sinha
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Fibroblast growth factor receptor (FGFR1-4) pathway alterations are rare in pediatric cancers (1-3%) but are enriched in certain specific subtypes of difficult to treat pediatric and AYA brain tumors. Some of the common oncogenic alterations include structural variants (fusions, duplications), mutations and amplifications. METHODS We describe here the clinico-pathological features and therapeutic outcomes of pediatric and AYA patients (ages 0-39yrs) with FGFR pathway altered gliomas diagnosed in the past 10yrs (2013-2023). Data was collected from review of patient charts. RESULTS We identified 13 patients with gliomas harboring an oncogenic FGFR alteration. Median age at diagnosis was 16yrs (range, 6-30yrs) and was more common in males (M: F-3:1). Seizures were the most common presenting symptom (N=5/13, 38%); all of these patients had cortical tumors, which were resected and seizures were adequately controlled. A biopsy only approach was done in more than half (N=7/13, 54%) of the patients. Pathological diagnosis included low grade glio-neuronal tumors in all but one of the patients, who had a high-grade glioma (Pilocytic astrocytoma N=6, Diffuse astrocytoma N=2, glio-neuronal tumors N=2, PLNTY N=2). FGFR alterations included oncogenic fusions (FGFR1-TACC1=1, FGFR2-TACC1=1, FGFR2-CTNNA3=2, FGFR3-TACC3=1), tandem duplications (FGFR1-TKD-ITD=3) and mutations (FGFR1- N546K=2, K654E=1, K656E=2). Co-occurring mutations were seen in 4 patients (H3.3-K27M=1, PIK3CA-E545K=1, PTPN11-G503V=1, PTPN11-E69K=1). Patients with symptomatic residual tumors (N=6, 46%) were treated with targeted therapies (Erdafitinib=3, Trametinib=1, Ponatinib / Everolimus=1, Dasatinib=1) and two patients received Radiation therapy. Erdafitinib was discontinued in one patient due to intra-tumoral bleed. Rest of the patients are tolerating the targeted therapy well and all of the patients are alive. CONCLUSION In summary, cortical tumors bearing FGFR alterations present with refractory seizures and are eminently treatable with surgical resection. Targeted therapy with FGFR specific inhibitors is tolerated well and updated response assessment of our patients will be presented in the meeting.